FasL gene knock-down therapy enhances the antiglioma immune response
Journal Title: Neuro-Oncology - Year 2010, Vol 12, Issue 5
Abstract
Malignant glioma is a lethal form of brain cancer that is very difficult to treat. The aggressive behavior of these neoplasms and their limited responsiveness to therapy has been attributed in part to the ability of these tumors to evade the immune system. Gliomas, like many other solid tumors, express components of numerous immune escape mechanisms, including immunosuppressive proteins such as TGF-β, IL-10, and FasL. Here, we show that FasL expression can support the growth of experimental intracranial glioma. We show that FasL is readily detected in human glioblastoma multiforme clinical specimens. FasL was found to be expressed by three well-characterized rat glioma cell lines (9L, F98, and C6) and glioma cell-derived FasL mediated the death of phytohemagglutinin-stimulated Jurkat T-lymphocytes when cocultured with glioma cells in vitro. We asked if inhibiting 9L-derived FasL altered the growth of experimental glioma. FasL expression knockdown using shRNA reduced the growth of subcutaneous and intracranial 9L gliomas by ∼50% in immune competent Fisher 344 rats. In contrast, FasL expression knockdown had no affect on the growth of intracranial 9L glioma in T-cell deficient athymic rats. Intracranial tumors derived from FasL knockdown 9L glioma cells contained up to 3-fold more tumor infiltrating T-cells than tumors derived from control 9L cells. These results demonstrate that down-regulating FasL expression and/or function in glial malignancies can enhance T-cell tumor infiltration and inhibit tumor growth. The findings suggest that targeting endogenous FasL in glial malignancies could enhance the efficacy of emerging immune-based treatment strategies.
Authors and Affiliations
Timothy Jansen, Betty Tyler, Joseph L. Mankowski, Violette Renard Recinos, Gustavo Pradilla, Federico Legnani, John Laterra, Alessandro Olivi
Keywords
Related Articles
- EP ID EP679607
- DOI 10.1093/neuonc/nop052
- Views 38
- Downloads 0
Editorial Board
Cetuximab, bevacizumab, and irinotecan for patients with primary glioblastoma and progression after radiation therapy and temozolomide: a phase II trial
The aim of this clinical trial was to investigate safety and efficacy when combining cetuximab with bevacizumab and irinotecan in patients with recurrent primary glioblastoma multiforme (GBM). Patients were included with...
Gliomas display a microRNA expression profile reminiscent of neural precursor cells
Gliomas express many genes that play a role in neural precursor cells (NPCs), but no direct comparison between glioma and stem cell (SC) gene expression profiles has been performed. To investigate the similarities and di...
Chloroquine-induced autophagic vacuole accumulation and cell death in glioma cells is p53 independent
Glioblastoma (GBM) is a high-grade central nervous system malignancy and despite aggressive treatment strategies, GBM patients have a median survival time of just 1 year. Chloroquine (CQ), an antimalarial lysosomotropic...
p53 in malignant glioma: 20 years later and still much to learn